1. Field of Invention
The invention relates to the field of pharmacology, in particular the treatment of dry eye syndrome and ocular surface disorders with delayed tear clearance using corticosteroid.
2. Description of Related Art
The human ocular surface is normally covered by a tear film that is composed of a superficial thin lipid layer (primarily derived from meibomian gland secretions), a middle bulk aqueous layer (consisting of proteins, electrolytes, and water secreted by lacrimal glands), and the innermost mucus layer derived from mucins secreted by the ocular surface epithelial cells..sup.1
A stable tear film ensures comfort and serves as the refractive optical surface of the eye. Furthermore, the tear film serves as a barrier for the ocular surface against microbial infection and inflammation from mechanical trauma..sup.1,2 Tear film deficiencies, referred to as dry eye, are a common clinical problem that can result from decreased secretion of tears by the lacrimal gland and/or increased evaporative loss due to a deficient lipid layer or blink abnormalities..sup.3 Patients with mild dry eye complain of annoying eye irritations. Those with severe dry eye, such as Sjogren's syndrome, may experience constant and disabling eye irritation, and develop ocular surface epithelial disease and sight-threatening sterile or microbial corneal ulceration..sup.4 The other reason that ocular irritation can occur is when the clearance of tears is delayed. Delayed tear clearance can be found in a number of other ocular surface disorders. Delayed tear clearance results in the accumulation of ocular irritants which can be derived from the environment (pollutants), medications (or preservatives), and cells (inflammatory mediators--to be described later).
For years it has been recognized that patients with dry eye develop pathologic changes of the ocular surface epithelial cells termed squamous metaplasia. Unreported research suggests that this process is the result of increased proliferation, abnormal differentiation, and inflammation of the ocular surface epithelial cells. In contrast to normal cells, these metaplastic cells do not produce the mucus that normally coats the ocular surface and forms a barrier against infection and mechanical trauma. This renders the ocular surface susceptible to damage from the mild trauma of desiccation blinking, rubbing, and foreign bodies (such as contact lenses).
In 1990, it was reported that a significantly greater percentage of patients with aqueous tear deficient dry eye than normal controls showed inflammatory cell infiltration of their conjunctival epithelium, and based on this finding, it was speculated that inflammation plays an important role in the pathogenesis of the conjunctival epithelial squamous metaplasia that develops in dry eye..sup.5 This hypothesis was confirmed by the abnormal production of an immune activation marker, intercellular adhesion molecule 1 (ICAM-1), and the inflammatory cytokine interleukin 6 (IL-6) by the conjunctival epithelial cells of patients with aqueous tear deficiency..sup.6 Expression of HLA-DR antigen by the conjunctival epithelium in the majority of patients (60%) with ocular irritation associated with aqueous tear deficiency as well as meibomian gland disease was subsequently noted, and these findings suggest that inflammation of the conjunctival epithelium may be the underlying cause for the ocular irritation experienced by patients suffering from all types of dry eye..sup.7 It is likely that this inflammation is enhanced when tear clearance is delayed.
Artificial tears are the current mainstay of therapy for dry eye..sup.3 They are aqueous solutions containing a number of different synthetic polymers to enhance their retention time on the ocular surface, and are available in both preserved and non-preserved formulations (summarized in Table 1). Although artificial tears provide temporary symptomatic improvement (typically 10 minutes or less), they have not been found to be effective in treating conjunctival squamous metaplasia.
Dry eye has not traditionally been considered to be an inflammatory disease. It is likely that practitioners have not considered the use of anti-inflammatory therapy for this reason as well as the potential risk of infection, corneal ulceration, elevated intraocular pressure, and cataract formation that may be associated with the use of topically applied corticosteroid. Our current concepts regarding the pathogenesis of the ocular surface disease and irritation that accompany syndromes with dry eye and delayed tear clearance suggested to us that the use of non-preserved topical corticosteroid may be effective, particularly for "pulse therapy" of the acute exacerbations that these patients often have.
The contents of all the documents cited herein are expressly incorporated by reference.